Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2121/00—Preparations for use in therapy
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to a class of fused pyridine derivatives, and to their use in therapy. More particularly, the present invention provides substituted pyrido[3,2- djpyrimidine and 1,5-naphthyridine derivatives. These compounds are selective inhibitors of phosphatidylinositol-4-kinase ⁇ ( ⁇ 4 ⁇ ) activity, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune and oncological disorders, in the treatment of viral diseases and malaria, and in the management of organ and cell transplant rejection.
• the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
• the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active
• WO 2013/034738 discloses that inhibitors of ⁇ 4 ⁇ activity are useful as medicaments for the treatment of autoimmune and inflammatory disorders, and organ and cell transplant rejection.
• Inhibitors of ⁇ 4 ⁇ have been identified as molecules with an ideal activity profile for the prevention, treatment and elimination of malaria (cf. C.W. McNamara et al., Nature, 2013, 504, 248-253).
• WO 2010/103130 describes a family of oxazolo[5,4-d]pyrimidine, thiazolo[5,4- ⁇ i]- pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives that are active in a range of assays, including the Mixed Lymphocyte Reaction (MLR) test, and are stated to be effective for the treatment of immune and autoimmune disorders, and organ and cell transplant rejection.
• MLR Mixed Lymphocyte Reaction
• WO 2011/147753 discloses the same family of compounds as having significant antiviral activity.
• WO 2012/035423 discloses the same family of compounds as having significant anticancer activity.
• WO 2013/024291, WO 2013/068458, WO 2014/053581 and WO 2014/096423 describe various series of fused pyrimidine derivatives that are stated to be of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune and oncological disorders, in the treatment of viral diseases, and in the management of organ and cell transplant rejection.
• PCT/EP2015/063051 and PCT/EP2015/063052 (published on 23 December 2015 as WO 2015/193167, WO 2015/193168 and WO 2015/193169 respectively) describe various series of fused bicyclic heteroaromatic derivatives that are stated to be selective inhibitors of ⁇ 4 ⁇ activity, and accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune and oncological disorders, in the treatment of viral diseases, and in the management of organ and cell transplant rejection.
• the compounds of the present invention are potent and selective inhibitors of ⁇ 4 ⁇ activity, inhibiting the kinase affinity of human ⁇ 4 ⁇ (IC 50 ) at concentrations of 50 ⁇ or less, generally of 20 ⁇ or less, usually of 5 ⁇ or less, typically of 1 ⁇ or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
• IC 50 kinase affinity of human ⁇ 4 ⁇
• the compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for human ⁇ 4 ⁇ relative to other human kinases.
• Certain compounds in accordance with the present invention are active as inhibitors when subjected to the Mixed Lymphocyte Reaction (MLR) test.
• MLR Mixed Lymphocyte Reaction
• the MLR test is predictive of immunosuppression or immunomodulation.
• certain compounds of the present invention display an IC 50 value of 10 ⁇ or less, generally of 5 ⁇ or less, usually of 2 ⁇ or less, typically of 1 ⁇ or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (again, the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
• the present invention provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:
• X represents N or CH
• M represents the residue of an optionally substituted saturated four-, five-, six- or seven-membered monocyclic ring containing one nitrogen atom and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom; or
• M represents the residue of an optionally substituted saturated or unsaturated 5- to
• M represents the residue of an optionally substituted saturated 5- to 9-membered bridged bicyclic ring system containing one nitrogen atom and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom; or
• M represents the residue of an optionally substituted saturated 5- to 9-membered spirocyclic ring system containing one nitrogen atom and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom;
• R 1 , R2 and R 3 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR a , -SR a , -SOR a , -S0 2 R a , -NR b R c , -CH 2 NR b R c , -NR c COR d , -CH 2 NR c COR d , -NR c C0 2 R d , -NHCONR b R c , -NR c S0 2 R e , -N(S0 2 R e ) 2 , -NHS0 2 NR b R c , -COR d , -C0 2 R d , -CONR b R c , -CON(OR a )R b or -S0 2 NR b R c ; or Ci_ 6 alkyl, C 3
• R 4 represents hydrogen, halogen, cyano, trifluoromethyl or Ci_ 6 alkyl
• R a represents hydrogen; or R a represents Ci_ 6 alkyl, aryl, aryl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents;
• R b and R c independently represent hydrogen or trifluoromethyl; or Ci_ 6 alkyl, C 3 -7 cycloalkyl, C 3 _ 7 cycloalkyl(Ci_ 6 )alkyl, aryl, aryl(Ci_ 6 )alkyl, C 3 _ 7 heterocycloalkyl, C 3 _ 7 heterocycloalkyl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
• R b and R c when taken together with the nitrogen atom to which they are both attached, represent azetidin-l-yl, pyrrolidin-l-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin- 1 -yl, homopiperidin- 1 -yl, homomorpholin-4-yl or homopiperazin- 1 -yl, any of which groups may be optionally substituted by one or more substituents;
• R d represents hydrogen; or Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, aryl, C 3 _ 7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and
• R e represents Ci_ 6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
• any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents.
• Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
• a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
• pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
• alkali metal salts e.g. sodium or potassium salts
• alkaline earth metal salts e.g. calcium or magnesium salts
• suitable organic ligands e.g. quaternary ammonium salts.
• solvates of the compounds of formula (I) above include within its scope solvates of the compounds of formula (I) above.
• Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
• the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.
• Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched Ci_ 6 alkyl groups, for example Ci_ 4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec -butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3- methylbutyl. Derived expressions such as "Ci_ 6 alkoxy", “Ci_ 6 alkylthio", "Ci_ 6 alkylsulfonyl” and "Ci_ 6 alkylamino" are to be construed accordingly.
• Suitable C 2 -6 alkenyl groups include vinyl, allyl and prop-l-en-2-yl.
• Suitable C3-7 cycloalkyl groups which may comprise benzo-fused analogues thereof, include cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl.
• Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
• Suitable aryl(Ci_6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
• Suitable heterocycloalkyl groups which may comprise benzo-fused analogues thereof, include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydro- isobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1 ,2,3,4-tetrahydroquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1 ,2,3,4-tetrahydroquinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomorpholinyl.
• heterocycloalkenyl groups examples include oxazolinyl.
• Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-3 ⁇ 4]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, imidazo[2,l-3 ⁇ 4]thiazolyl, benzimidazolyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]- pyridinyl, imidazo[4,5-£]pyridinyl, pur
• halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
• Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
• each individual atom present in formula (I), or in the formulae depicted hereinafter may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.
• each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter may be present as a 1 H, 2 H (deuterium) or 3 H (tritium) atom, preferably 1 H.
• each individual carbon atom present in formula (I), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
• X represents N. In another embodiment, X represents CH.
• Individual sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IA) and (IB):
• M represents the residue of an optionally substituted saturated four-, five-, six- or seven-membered monocyclic ring containing one nitrogen atom and 0, 1 , 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom.
• M represents the residue of an optionally substituted saturated four-membered monocyclic ring. In a second embodiment, M represents the residue of an optionally substituted saturated five-membered monocyclic ring. In a third embodiment, M represents the residue of an optionally substituted saturated six- membered monocyclic ring. In a fourth embodiment, M represents the residue of an optionally substituted saturated seven-membered monocyclic ring.
• the monocyclic ring of which M is the residue contains one nitrogen atom and no additional heteroatoms (i.e. it is an optionally substituted azetidin-1- yl, pyrrolidin-l-yl, piperidin-l-yl or azepan-l-yl ring).
• the monocyclic ring of which M is the residue contains one nitrogen atom and one additional heteroatom selected from N, O and S.
• the monocyclic ring of which M is the residue contains one nitrogen atom and two additional heteroatoms selected from N, O and S, of which not more than one is O or S.
• the monocyclic ring of which M is the residue contains one nitrogen atom and three additional heteroatoms selected from N, O and S, of which not more than one is O or S.
• Typical values of the monocyclic ring of which M is the residue include azetidin- 1-yl, pyrrolidin-l-yl, imidazolidin-l-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4- yl, piperazin-l-yl, azepan-l-yl and [l,4]diazepan-l-yl, any of which rings may be optionally substituted by one or more substituents.
• Suitable values of the monocyclic ring of which M is the residue include azetidin- 1 -yl, morpholin-4-yl, piperazin-l-yl and azepan-l-yl, any of which rings may be optionally substituted by one or more substituents.
• a particular value of the monocyclic ring of which M is the residue is optionally substituted piperazin-l-yl.
• M represents the residue of an optionally substituted saturated or unsaturated 5- to 10-membered fused bicyclic ring system containing one nitrogen atom and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom.
• M represents the residue of an optionally substituted saturated or unsaturated five-membered fused bicyclic ring system.
• M represents the residue of an optionally substituted saturated or unsaturated six-membered fused bicyclic ring system.
• M represents the residue of an optionally substituted saturated or unsaturated seven- membered fused bicyclic ring system.
• M represents the residue of an optionally substituted saturated or unsaturated eight-membered fused bicyclic ring system.
• M represents the residue of an optionally substituted saturated or unsaturated nine-membered fused bicyclic ring system.
• M represents the residue of an optionally substituted saturated or unsaturated ten-membered fused bicyclic ring system.
• the fused bicyclic ring system of which M is the residue is saturated. In a second embodiment, the fused bicyclic ring system of which M is the residue is unsaturated.
• the fused bicyclic ring system of which M is the residue contains one nitrogen atom and no additional heteroatoms.
• the fused bicyclic ring system of which M is the residue contains one nitrogen atom and one additional heteroatom selected from N, O and S.
• the fused bicyclic ring system of which M is the residue contains one nitrogen atom and two additional heteroatoms selected from N, O and S, of which not more than one is O or S.
• the fused bicyclic ring system of which M is the residue contains one nitrogen atom and three additional heteroatoms selected from N, O and S, of which not more than one is O or S.
• Typical values of the fused bicyclic ring system of which M is the residue include 1 ,2,3,4,6,7,8,8a-octahydropyrrolo[l ,2-a]pyrazin-2-yl and 4,5,6,7-tetrahydropyrazolo[l ,5- a]pyrazin-5-yl, either of which ring systems may be optionally substituted by one or more substituents.
• Suitable values of the fused bicyclic ring system of which M is the residue include l,2,3,4,6,7,8,8a-octahydropyrrolo[l,2-a]pyrazin-2-yl, which ring system may be optionally substituted by one or more substituents.
• M represents the residue of an optionally substituted saturated 5- to 9-membered bridged bicyclic ring system containing one nitrogen atom and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom.
• M represents the residue of an optionally substituted saturated five-membered bridged bicyclic ring system.
• M represents the residue of an optionally substituted saturated six-membered bridged bicyclic ring system.
• M represents the residue of an optionally substituted saturated seven-membered bridged bicyclic ring system.
• M represents the residue of an optionally substituted saturated eight- membered bridged bicyclic ring system.
• M represents the residue of an optionally substituted saturated nine -membered bridged bicyclic ring system.
• the bridged bicyclic ring system of which M is the residue contains one nitrogen atom and no additional heteroatoms.
• the bridged bicyclic ring system of which M is the residue contains one nitrogen atom and one additional heteroatom selected from N, O and S.
• the bridged bicyclic ring system of which M is the residue contains one nitrogen atom and two additional heteroatoms selected from N, O and S, of which not more than one is O or S.
• the bridged bicyclic ring system of which M is the residue contains one nitrogen atom and three additional heteroatoms selected from N, O and S, of which not more than one is O or S.
• Typical values of the bridged bicyclic ring system of which M is the residue include 3-azabicyclo[3.1.0]hexan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 6- azabicyclo[3.2.0]heptan-6-yl, 3-azabicyclo[3.1.l]heptan-3-yl, 3-azabicyclo[4.1.0]heptan- 3-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, 3-azabicyclo[3.2.1]octan-3-yl, 8-azabicyclo- [3.2.1 ]octan-8-yl, 3-oxa-8-azabicyclo[3.2.1 ]octan-8-yl, 3 ,8-diazabicyclo[3.2.1 ]octan-3-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 3,6-diazabicyclo
• M represents the residue of an optionally substituted saturated 5- to 9-membered spirocyclic ring system containing one nitrogen atom and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom.
• M represents the residue of an optionally substituted saturated five-membered spirocyclic ring system.
• M represents the residue of an optionally substituted saturated six-membered spirocyclic ring system.
• M represents the residue of an optionally substituted saturated seven-membered spirocyclic ring system.
• M represents the residue of an optionally substituted saturated eight-membered spirocyclic ring system.
• M represents the residue of an optionally substituted saturated nine- membered spirocyclic ring system.
• the spirocyclic ring system of which M is the residue contains one nitrogen atom and no additional heteroatoms.
• the spirocyclic ring system of which M is the residue contains one nitrogen atom and one additional heteroatom selected from N, O and S.
• the spirocyclic ring system of which M is the residue contains one nitrogen atom and two additional heteroatoms selected from N, O and S, of which not more than one is O or S.
• the spirocyclic ring system of which M is the residue contains one nitrogen atom and three additional heteroatoms selected from N, O and S, of which not more than one is O or S.
• Typical values of the spirocyclic ring system of which M is the residue include 5- azaspiro[2.3]hexan-5-yl, 5-azaspiro[2.4]heptan-5-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6- azaspiro[3.3]heptan-6-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 2-oxa-6-azaspiro[3.5]nonan-2- yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl and 2-oxa-7-azaspiro[3.5]nonan-7-yl, any of which ring systems may be optionally substituted by one or more substituents.
• Suitable values of the spirocyclic ring system of which M is the residue include 2- oxa-6-azaspiro[3.3]heptan-6-yl, which ring system may be optionally substituted
• the cyclic moiety of which M is the residue is substituted by one or more substituents. In one subset of that embodiment, the cyclic moiety of which M is the residue is monosubstituted. In another subset of that
• the cyclic moiety of which M is the residue is disubstituted.
• Typical examples of optional substituents on the cyclic moiety of which M is the residue include halogen, Ci_ 6 alkyl, benzyl, heteroaryl, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_ 6 alkoxy(Ci_6)alkyl, Ci_ 6 alkylthio, Ci_ 6 alkylsulfonyl, hydroxy, hydroxy(Ci_6)alkyl, cyano, trifluoromethyl, oxo, C 2 -6 alkylcarbonyl, hydroxy(Ci_6)alkyl- carbonyl, di(Ci_6)alkylamino(Ci_6)alkylcarbonyl, carboxy, carboxy(Ci_ 6 )alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl, amino, amino(Ci_6)alkyl, Ci_ 6 alkylamino, di(Ci_6)al
• Suitable examples of optional substituents on the cyclic moiety of which M is the residue include Ci_ 6 alkyl, C 2 _ 6 alkylcarbonyl, C 2 _ 6 alkoxycarbonyl, (C 1-6 alkoxy)(Ci_6 alkyl)phenylaminocarbonyl, (C 1-6 alkoxy)(Ci_6 alkyl)pyridinylaminocarbonyl, [di(C 1-6 )- alkylamino] (Ci_6 alkyl)pyridinylaminocarbonyl and (dihaloazetidinyl)(Ci_6 alkyl)- pyridiny laminocarbony 1.
• Typical examples of specific substituents on the cyclic moiety of which M is the residue include fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, benzyl, pyridinyl, pyrazinyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulfonyl, hydroxy, hydroxymethyl, hydroxy ethyl, cyano, trifluoromethyl, oxo, acetyl, ethylcarbonyl, tert-butylcarbonyl, hydroxyacetyl, dimethyl- aminoacetyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy- carbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, amino, aminomethyl, methyl- amino,
• Suitable examples of specific substituents on the cyclic moiety of which M is the residue include methyl, acetyl, ethoxycarbonyl, (methoxy)(methyl)phenylaminocarbonyl, (methoxy)(methyl)pyridinylaminocarbonyl, (dimethylamino)(methyl)pyridinylamino- carbonyl and (difluoroazetidinyl)(methyl)pyridinylaminocarbonyl.
• Typical values of the cyclic moiety of which M is the residue include 3,3-difluoro- azetidin-l-yl, pyrrolidin-l-yl, 3-hydroxypyrrolidin-l-yl, 3-(acetylamino)pyrrolidin-l-yl,
• Suitable values of the cyclic moiety of which M is the residue include 4-acetyl- piperazin- 1 -yl, 4-(ethoxycarbonyl)piperazin- 1 -yl, 4-[(4-methoxy-2-methylphenyl)amino- carbonyljpiperazin- 1 -yl, 4- [(4-methoxy-2-methylphenyl)aminocarbonyl] -2-methyl- piperazin-l-yl, 4-[(6-methoxy-2-methylpyridin-3-yl)aminocarbonyl]-2-methylpiperazin- 1 -yl, 4- ⁇ [6-(dimethylamino)-2-methylpyridin-3 -yl] aminocarbonyl ⁇ -2-methylpiperazin- 1 - yl and 4- ⁇ [6-(3,3-difluoroazetidin-l-yl)-2-methylpyridin-3-yl]aminocarbonyl ⁇ -2-methyl
• R 1 represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR a , -SR a , -S0 2 R a , -NR b R c , -CH 2 R b R c , -NR c COR d , -CH 2 NR c COR d , -NR c C0 2 R d , -NHCONR b R c , -NR c S0 2 R e , -NHS0 2 NR b R c , -COR d , -C0 2 R d , -CONR b R c , -CON(OR a )R b or -S0 2 NR b R c ; or R 1 represents Ci_ 6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
• R 1 represents hydrogen, -OR a , -SR a , -S0 2 R a , -NR b R c or -NR c COR d ; or
• R 1 represents Ci_ 6 alkyl, which group may be optionally substituted by one or more substituents.
• Typical values of R 1 include hydrogen, -OR a , -SR a , -S0 2 R a and -NR b R c .
• Suitable values of R 1 include hydrogen and -NR b R c .
• R 1 represents hydrogen. In a second embodiment, R 1 represents cyano. In a third embodiment, R 1 represents -OR a . In a fourth embodiment, R 1 represents -SR a . In a fifth embodiment, R 1 represents -S0 2 R a . In a sixth embodiment, R 1 represents -NR b R c . In a seventh embodiment, R 1 represents -NR c COR d . In an eighth embodiment, R 1 represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R 1 represents optionally substituted methyl.
• R 1 examples include one or more substituents independently selected from halogen, cyano, nitro, Ci_ 6 alkyl, trifluoromethyl,
• substituents on R 1 include one or more substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulfonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, ethoxycarbonyl- amino, benzyloxycarbonylammo, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy,
• methoxycarbonyl aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
• R 2 represents hydrogen, cyano, hydroxy, trifluoromethyl, -NR c C0 2 R d , -COR d , -C0 2 R d , -CONR b R c or -CON(OR a )R b ; or R 2 represents Ci.g alkyl, C 3 _ 7 cycloalkyl, aryl, C 3 _ 7 heterocycloalkyl, C 3 _ 7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
• R 2 represents hydrogen; or R 2 represents aryl, C 3 _ 7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more
• R represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.
• R represents hydrogen; or R represents aryl, which group may be optionally substituted by one or more substituents.
• R 2 represents hydrogen. In a second embodiment, R 2 represents cyano. In a third embodiment, R represents hydroxy. In a fourth
• R 2 represents trifluoromethyl. In a fifth embodiment, R 2 represents
• R 2 represents -NR c C0 2 R d .
• R 2 represents -COR d .
• R 2 represents -C0 2 R d .
• R 2 represents -CONR b R c .
• R 2 represents -CON(OR a )R b .
• R 2 represents optionally substituted Ci_ 6 alkyl. In a first aspect of that embodiment, R represents
• R represents
• R represents
• R represents optionally substituted C 3 _ 7 cycloalkyl. In a first aspect of that embodiment, R represents unsubstituted C 3 _ 7 2
• R represents monosubstituted C 3 -7 cycloalkyl. In a third aspect of that embodiment, R represents disubstituted C 3 -7
• R represents optionally substituted aryl.
• R represents unsubstituted aryl.
• R represents monosubstituted aryl.
• R represents disubstituted aryl. In a thirteenth embodiment, R represents optionally substituted C 3 -7 heterocycloalkyl. In a first aspect of that embodiment, R represents unsubstituted C 3 -7 heterocycloalkyl. In a second aspect of that embodiment, R represents
• R represents disubstituted C3-7 heterocycloalkyl.
• R represents optionally substituted C3_7 heterocycloalkenyl.
• R represents unsubstituted C3-7 heterocycloalkenyl.
• R represents monosubstituted C3_7 heterocycloalkenyl.
• R represents disubstituted C3_7 heterocycloalkenyl.
• R represents optionally substituted heteroaryl.
• R represents unsubstituted heteroaryl. In a second aspect of that embodiment, R represents monosubstituted heteroaryl. In a third aspect of that
• R represents disubstituted heteroaryl.
• R represents optionally substituted Ci_ 6 alkyl
• suitable values include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, any of which groups may be optionally substituted by one or more substituents.
• Selected values include methyl, hydroxymethyl, chloropropyl and isobutyl.
• Particular values include methyl and isobutyl, especially methyl.
• R represents optionally substituted C3-7 cycloalkyl
• a suitable value is cyclohexyl, optionally substituted by one or more substituents.
• R represents optionally substituted aryl
• a suitable value is phenyl, optionally substituted by one or more substituents.
• R represents optionally substituted C3-7 heterocycloalkyl
• typical values include azetidinyl, dihydroisobenzofuranyl, pyrrolidinyl, indolinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, any of which groups may be optionally substituted by one or more substituents. 2
• R represents optionally substituted C3-7 heterocycloalkenyl
• a typical value is oxazolinyl, optionally substituted by one or more substituents. Suitable values include oxazolinyl, methyloxazolinyl, isopropyloxazolinyl and dimethyloxazolinyl.
• R represents optionally substituted heteroaryl
• typical values include furyl, thienyl, pyrrolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazo[l,5-a]pyridinyl, oxadiazolyl, benzoxadiazolyl, thiadiazolyl, triazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, any of which groups may be optionally substituted by one or more substituents.
• R represents hydrogen; or R represents phenyl, dihydroisobenzofuranyl, indolinyl, indazolyl, imidazo[l,5-a]pyridinyl, benzoxadiazolyl, [l,2,4]triazolo[4,3-a]pyridinyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.
• R represents hydrogen; or R represents phenyl, which group may be optionally substituted by one or more substituents.
• Typical examples of optional substituents on R include one or more substituents independently selected from halogen, cyano, nitro, Ci_ 6 alkyl, trifluoromethyl, hydroxy, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulfmyl, Ci_ 6 alkylsulfonyl, oxo, amino, Ci_ 6 alkylamino, di(Ci_6)alkylamino, C 2 _ 6 alkylcarbonylamino, C 2 _6 alkoxycarbonylamino, Ci_ 6 alkylsulfonylamino, formyl, C 2 _ 6 alkylcarbonyl, carboxy, C 2 _6 alkoxycarbonyl, aminocarbonyl, Ci_ 6 alkylaminocarbonyl, di(Ci_6)alkylamino- carbonyl, aminosulfonyl, Ci_ 6 alkylaminosul
• Suitable examples of optional substituents on R include one or more substituents independently selected from Ci_ 6 alkoxy.
• substituents on R include one or more substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethyl- aminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
• Suitable examples of specific substituents on R include one or more substituents independently selected from methoxy. 2
• Typical values of R include hydrogen, cyano, hydroxy, trifluoromethyl,
• Suitable values of R include hydrogen and dimethoxyphenyl.
• R 3 represents hydrogen, cyano, hydroxy, trifluoromethyl, -NR c C0 2 R d , -COR d , -C0 2 R d , -CONR b R c or -CON(OR a )R b ; or R 3 represents Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, aryl, C 3 _ 7 heterocycloalkyl, C 3 _ 7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
• R 3 represents hydrogen; or R 3 represents aryl, C 3 _ 7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more
• R represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.
• R 3 represents hydrogen. In a second embodiment, R 3 represents cyano. In a third embodiment, R represents hydroxy. In a fourth
• R 3 represents trifluoromethyl. In a fifth embodiment, R 3 represents
• R 3 represents -NR c C0 2 R d .
• R 3 represents -COR d .
• R 3 represents -C0 2 R d .
• R 3 represents -CONR b R c .
• R 3 represents -CON(OR a )R b .
• R 3 represents optionally substituted Ci_ 6 alkyl.
• R represents unsubstituted Ci_ 6 alkyl.
• R represents
• R represents disubstituted Ci_ 6 alkyl.
• R represents disubstituted Ci_ 6 alkyl.
• R represents optionally substituted C 3 _ 7 cycloalkyl.
• R represents unsubstituted C 3 _ 7 cycloalkyl.
• R represents monosubstituted C 3 _ 7 cycloalkyl.
• R represents disubstituted C 3 _ 7 cycloalkyl.
• R represents optionally substituted aryl.
• R represents unsubstituted aryl.
• R represents monosubstituted aryl.
• a third aspect of that embodiment represents monosubstituted aryl.
• a third aspect of that embodiment represents optionally substituted aryl. In a first aspect of that embodiment, R represents unsubstituted aryl. In a second aspect of that embodiment, R represents monosubstituted aryl. In a third aspect of that embodiment,
• R 3 represents disubstituted aryl. In a thirteenth embodiment, R 3 represents optionally substituted C 3 -7 heterocycloalkyl. In a first aspect of that embodiment, R represents unsubstituted C 3 -7 heterocycloalkyl. In a second aspect of that embodiment, R represents monosubstituted C 3 _ 7 heterocycloalkyl. In a third aspect of that embodiment, R represents disubstituted C 3 _ 7 heterocycloalkyl. In a fourteenth embodiment, R represents optionally substituted C 3 _ 7 heterocycloalkenyl. In a first aspect of that embodiment, R represents unsubstituted C 3 _ 7 heterocycloalkenyl.
• R represents monosubstituted C 3 _ 7 heterocycloalkenyl. In a third aspect of that embodiment, R represents disubstituted C 3 _ 7 heterocycloalkenyl. In a fifteenth embodiment, R represents optionally substituted heteroaryl. In a first aspect of that embodiment, R represents unsubstituted heteroaryl. In a second aspect of that embodiment, R represents monosubstituted heteroaryl. In a third aspect of that embodiment, R represents disubstituted heteroaryl.
• R represents optionally substituted Ci_ 6 alkyl
• suitable values include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, any of which groups may be optionally substituted by one or more substituents.
• Selected values include methyl, hydroxymethyl, chloropropyl and isobutyl.
• Particular values include methyl and isobutyl, especially methyl.
• R represents optionally substituted C 3 _ 7 cycloalkyl
• a suitable value is cyclohexyl, optionally substituted by one or more substituents.
• R represents optionally substituted aryl
• a suitable value is phenyl, optionally substituted by one or more substituents.
• R represents optionally substituted C 3 _ 7 heterocycloalkyl
• typical values include azetidinyl, dihydroisobenzofuranyl, pyrrolidinyl, indolinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, any of which groups may be optionally substituted by one or more substituents.
• R represents optionally substituted C 3 _ 7 heterocycloalkenyl
• a typical value is oxazolinyl, optionally substituted by one or more substituents. Suitable values include oxazolinyl, methyloxazolinyl, isopropyloxazolinyl and dimethyloxazolinyl.
• R represents optionally substituted heteroaryl
• typical values include furyl, thienyl, pyrrolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazo[l,5-a]pyridinyl, oxadiazolyl, benzoxadiazolyl, thiadiazolyl, triazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, any of which groups may be optionally substituted by one or more substituents.
• R represents hydrogen, phenyl, dihydroisobenzofuranyl, indolinyl, indazolyl, imidazo[l,5-a]pyridinyl, benzoxadiazolyl, [l,2,4]triazolo[4,3-a]- pyridinyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.
• Typical examples of optional substituents on R include one or more substituents independently selected from halogen, cyano, nitro, Ci_ 6 alkyl, trifluoromethyl, hydroxy, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulfmyl, Ci_ 6 alkylsulfonyl, oxo, amino, Ci_ 6 alkylamino, di(Ci_6)alkylamino, C 2 _ 6 alkylcarbonylamino, C 2 _6 alkoxycarbonylamino, Ci_ 6 alkylsulfonylamino, formyl, C 2 _ 6 alkylcarbonyl, carboxy, C 2 _6 alkoxycarbonyl, aminocarbonyl, Ci_ 6 alkylaminocarbonyl, di(Ci_6)alkylamino- carbonyl, aminosulfonyl, Ci_ 6 alkylaminosul
• substituents on R include one or more substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethyl- aminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
• Typical values of R include hydrogen, cyano, hydroxy, trifluoromethyl,
• R 4 represents hydrogen or Ci_ 6 alkyl.
• R 4 represents hydrogen. In a second embodiment, R 4 represents halogen, especially fluoro or chloro. In a first aspect of that embodiment, R 4 represents fluoro. In a second aspect of that embodiment, R 4 represents chloro. In a third embodiment, R 4 represents cyano. In a fourth embodiment, R 4 represents trifluoromethyl. In a fifth embodiment, R 4 represents Ci_ 6 alkyl, especially methyl.
• Typical values of R 4 include hydrogen, chloro, cyano, trifluoromethyl and methyl. Suitable values of R 4 include hydrogen and methyl.
• Suitable substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_ 6 alkoxy(Ci_ 6 )alkyl, Ci_ 6 alkylthio, Ci_ 6 alkylsulfinyl, Ci_ 6
• Ci_ 6 alkylsulfonimidoyl N,5'-di(Ci_6)alkylsulfonimidoyl, hydroxy, hydroxy(Ci_6)alkyl, amino(Ci_6)alkyl, cyano, trifluoromethyl, oxo, C 2 -6 alkylcarbonyl, carboxy, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkylcarbonyloxy, amino, Ci_ 6 alkylamino, di- (Ci_6)alkylamino, phenylamino, pyridinylamino, C 2 _ 6 alkylcarbonylamino, C 2 _ 6 alkylcarbonylamino(Ci_6)alkyl, C 2 _ 6 alkoxycarbonylamino, Ci_ 6 alkylsulfonylamino, aminocarbonyl, Ci_ 6 alkylaminocarbonyl and di(Ci
• Typical examples of specific substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, methylsulfonimidoyl, N ⁇ -dimethyl- sulfonimidoyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, cyano, trifluoro- methyl, oxo, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, amino, methylamino, ethylamino
• R a represents hydrogen; or R a represents Ci_ 6 alkyl, aryl(Ci_ 6 )alkyl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
• R a represents Ci_ 6 alkyl, aryl(Ci_6)alkyl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
• Apposite values of R a include hydrogen; and methyl, ethyl, benzyl or isoindolyl- propyl, any of which groups may be optionally substituted by one or more substituents.
• R a Selected values of R a include methyl, ethyl, benzyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.
• R a Selected examples of suitable substituents on R a include Ci_ 6 alkoxy and oxo.
• R a Selected examples of specific substituents on R a include methoxy and oxo.
• R a represents hydrogen. In another embodiment, R a represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R a ideally represents unsubstituted Ci_ 6 alkyl, especially methyl. In another aspect of that embodiment, R a ideally represents substituted Ci_ 6 alkyl, e.g. methoxyethyl. In another embodiment, R a represents optionally substituted aryl. In one aspect of that embodiment, R a represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, R a represents monosubstituted aryl, especially methylphenyl.
• R a represents optionally substituted aryl(Ci_6)alkyl, ideally unsubstituted aryl(Ci_6)alkyl, especially benzyl.
• R a represents optionally substituted heteroaryl.
• R a represents optionally substituted heteroaryl(Ci_6)alkyl, e.g.
• R a examples include methyl, methoxyethyl, benzyl and dioxoisoindolyl- propyl.
• R a represents hydrogen or Ci_ 6 alkyl.
• R a Individual values of R a include hydrogen and methyl.
• R b represents hydrogen or trifluoromethyl; or R b represents Ci_6 alkyl, C 3 -7 cycloalkyl, C 3 -7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C 3 -7 hetero- cycloalkyl, C 3 _7 heterocycloalkyl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
• R b represents hydrogen; or R b represents aryl(Ci_6)alkyl or heteroaryl(Ci_6)alkyl, either of which groups may be optionally substituted by one or more substituents.
• R b represents hydrogen or trifluoromethyl; or R b represents methyl, ethyl, /? -propyl, isopropyl, /? -butyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentyl- methyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, azetidinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, pyrrolidinyleth
• Typical examples of optional substituents on R b include Ci_ 6 alkyl, Ci_ 6 alkoxy, Ci_6 alkylthio, Ci_ 6 alkylsulfmyl, Ci_ 6 alkylsulfonyl, Ci_ 6 alkylsulfonimidoyl, N,S-di- (Ci_6)alkylsulfonimidoyl, hydroxy, cyano, C 2 -6 alkoxycarbonyl, di(Ci_6)alkylamino and C 2 _6 alkoxy carbonylamino.
• Typical examples of specific substituents on R b include methyl, methoxy, methylthio, methylsulfinyl, methylsulfonyl, methylsulfonimidoyl, N ⁇ -dimethyl- sulfonimidoyl, hydroxy, cyano, tert-butoxycarbonyl, dimethylamino and tert- butoxy carbonylamino .
• R b Typical values of R b include hydrogen, methyl, methoxy ethyl, methylthioethyl, methylsulfinylethyl, methylsulfonylethyl, hydroxyethyl, cyanoethyl, dimethylaminoethyl, fert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, methylsulfonylbenzyl, methyl- sulfonimidoylbenzyl, N ⁇ -dimethylsulfonimidoylbenzyl, pyrrolidinyl, tert-butoxycarbonyl- pyrrolidinyl, morpholinylpropyl, methylisoxazolylmethyl, dimethylthiazolylmethyl, dimethylpyrazolylmethyl, methyloxadiazolylmethyl and methylpyridinylmethyl.
• Suitable values of R b include hydrogen and methylpyridinylmethyl.
• R b represents hydrogen. In another embodiment, R b is other than hydrogen.
• R c include hydrogen; or Ci_ 6 alkyl, C 3 -7 cycloalkyl or C 3 -7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
• R c represents hydrogen, Ci_ 6 alkyl or C 3 _ 7 cycloalkyl.
• R c include hydrogen; or methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.
• Selected examples of suitable substituents on R c include C 2 -6 alkylcarbonyl and C 2 -6 alkoxycarbonyl.
• R c Selected examples of specific substituents on R c include acetyl and tert- butoxycarbonyl.
• R c include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl and tert-butoxycarbonylpiperidinyl.
• R c represents hydrogen or Ci_ 6 alkyl.
• R c is hydrogen.
• R c represents Ci_ 6 alkyl, especially methyl or ethyl, particularly methyl.
• R c represents C 3 _ 7 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• the moiety -NR b R c may suitably represent azetidin-l-yl, pyrrolidin- 1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1- yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl,
• homomorpholin-4-yl or homopiperazin-l-yl any of which groups may be optionally substituted by one or more substituents.
• Selected examples of suitable substituents on the heterocyclic moiety -NR b R c include Ci_ 6 alkyl, Ci_ 6 alkylsulfonyl, hydroxy, hydroxy(Ci_ 6 )alkyl, amino(Ci_6)alkyl, cyano, oxo, C 2 _6 alkylcarbonyl, carboxy, C 2 _6 alkoxycarbonyl, amino, C 2 _6 alkylcarbonyl- amino, C 2 _6 alkylcarbonylamino(Ci_6)alkyl, C 2 _6 alkoxycarbonylamino, Ci_ 6 alkyl- sulfonylamino and aminocarbonyl.
• Selected examples of specific substituents on the heterocyclic moiety -NR b R c include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, fert-butoxy- carbonylamino, methylsulfonylamino and aminocarbonyl.
• R c Specific values of the moiety -NR b R c include azetidin-l-yl, hydroxyazetidin-l-yl, hydroxymethylazetidin- 1 -yl, (hydroxy)(hydroxymethyl)azetidin- 1 -yl, aminomethyl- azetidin-l-yl, cyanoazetidin-l-yl, carboxyazetidin-l-yl, aminoazetidin-l-yl,
• R d represents hydrogen; or Ci_ 6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
• R d examples include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.
• R d Selected examples of suitable substituents on R d include halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, oxo, C 2 _ 6 alkylcarbonyloxy and di(Ci_6)alkylamino.
• R d Selected examples of particular substituents on R d include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.
• R d represents hydrogen. In another embodiment, R d represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R d ideally represents unsubstituted Ci_ 6 alkyl, e.g. methyl, ethyl, isopropyl, 2-methylpropyl or tert- butyl, especially methyl or ethyl, particularly methyl. In another aspect of that embodiment, R d ideally represents substituted Ci_ 6 alkyl, e.g. substituted methyl or substituted ethyl, including acetoxymethyl, dimethylaminomethyl and trifluoroethyl. In another embodiment, R d represents optionally substituted aryl.
• R d represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, R d represents monosubstituted aryl, especially methylphenyl. In a further aspect of that embodiment, R d represents disubstituted aryl, e.g. dimethoxyphenyl. In a further embodiment, R d represents optionally substituted heteroaryl, e.g. thienyl, chlorothienyl, methylthienyl, methylimidazolyl or thiazolyl. In another embodiment, R d represents optionally substituted C 3 _ 7 cycloalkyl, e.g. cyclopropyl or cyclobutyl. In a further embodiment, R d represents optionally substituted C 3 _ 7 heterocycloalkyl, e.g.
• R d selected examples include hydrogen, methyl, ethyl, acetoxymethyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, dimethoxyphenyl, thiazolidinyl,
• R d represents hydrogen or Ci_ 6 alkyl.
• R d Individual values of R d include hydrogen, methyl and ethyl. A particular value of R d is ethyl.
• R e represents Ci_ 6 alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.
• R e Selected examples of suitable substituents on R e include Ci_ 6 alkyl, especially methyl.
• R e represents optionally substituted Ci_ 6 alkyl, ideally unsubstituted Ci_ 6 alkyl, e.g. methyl or propyl, especially methyl.
• R e represents optionally substituted aryl.
• R e represents unsubstituted aryl, especially phenyl.
• R e represents monosubstituted aryl, especially methylphenyl.
• R e represents optionally substituted heteroaryl.
• Selected values of R e include methyl, propyl and methylphenyl.
• X, M, R 2 , R 3 , R 4 and R b are as defined above.
• the compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments. These include inflammatory, autoimmune and oncological disorders; viral diseases and malaria; and organ and cell transplant rejection.
• Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders and organ-specific autoimmune disorders.
• Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, vasculitis, polymyositis, scleroderma, multiple sclerosis, ankylosing spondylitis, rheumatoid arthritis and Sjogren's syndrome.
• Autoimmune endocrine disorders include thyroiditis.
• Organ-specific autoimmune disorders include Addison's disease, haemolytic or pernicious anaemia, glomerulonephritis (including Goodpasture's syndrome), Graves' disease, idiopathic thrombocytopenic purpura, insulin-dependent diabetes mellitus, juvenile diabetes, uveitis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis and spontaneous infertility.
• Oncological disorders which may be acute or chronic, include proliferative disorders, especially cancer, in animals, including mammals, especially humans.
• cancers include haematological malignancy (including leukaemia and lymphoma) and non-haematological malignancy (including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma).
• Chronic leukaemia may be myeloid or lymphoid.
• Varieties of leukaemia include lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL), hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML),
• lymphoma myelodysplastic syndrome, chronic neutrophilic leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia, multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocyte leukaemia, promyelocytic leukaemia and erythroleukaemia.
• Varieties of lymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, MALT1 lymphoma and marginal zone lymphoma.
• Non-haematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, skin, bone, stomach and muscle.
• Viral diseases include infections caused by various families of virus, including the Retroviridae, Flaviviridae, Picornaviridae.
• Various genera within the Retroviridae family include Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus,
• Epsilonretrovirus, Lentivirus and Spumavirus Members of the Lentivirus genus include human immunodeficiency virus 1 (HIV-1) and human immunodeficiency virus 2 (HIV-2).
• Flavivirus, Pestivirus, Hepacivirus and Hepatitis G Virus Members of the Flavivirus genus include Dengue fever virus, yellow fever virus, West Nile encephalitis virus and Japanese encephalitis virus.
• Members of the Pestivirus genus include bovine viral diarrhoea virus (BVDV), classical swine fever virus and border disease virus 2 (BDV-2).
• Members of the Hepacivirus genus include hepatitis C virus (HCV).
• Various genera within the Picornaviridae family include Aphthovirus,
• Parechovirus Parechovirus, Sapelovirus, Senecavirus, Teschovirus and Tremovirus.
• Members of the Enterovirus genus include poliovirus, coxsackie A virus, coxsackie B virus and rhinovirus.
• Organ transplant rejection includes the rejection of transplanted or grafted organs or cells (both allografts and xenografts), including graft-versus-host reaction disease.
• organ as used herein means all organs or parts of organs in mammals, particularly humans, including kidney, lung, bone marrow, hair, cornea, eye (vitreous), heart, heart valve, liver, pancreas, blood vessel, skin, muscle, bone, intestine and stomach.
• rejection as used herein means all reactions of the recipient body or the transplanted organ which ultimately lead to cell or tissue death in the transplanted organ, or adversely affect the functional ability and viability of the transplanted organ or the recipient. In particular, this means acute and chronic rejection reactions.
• Cell transplant rejection includes the rejection of cell transplants and xenotransplantation.
• the major hurdle for xenotransplantation is that even before the T lymphocytes (responsible for the rejection of allografts) are activated, the innate immune system (especially T-independent B lymphocytes and macrophages) is activated. This provokes two types of severe and early acute rejection, referred to as hyperacute rejection and vascular rejection respectively.
• Conventional immunosuppressant drugs, including cyclosporine A are ineffective in xenotransplantation.
• the compounds in accordance with the present invention are not liable to this drawback.
• the ability of the compounds of this invention to suppress T-independent xeno-antibody production as well as macrophage activation may be demonstrated by their ability to prevent xenograft rejection in athymic, T-deficient mice receiving xenogenic hamster-heart grafts.
• the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
• compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
• compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with
• binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
• fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
• lubricants e.g. magnesium stearate, talc or silica
• disintegrants e.g. potato starch or sodium glycollate
• wetting agents e.g. sodium lauryl sulfate.
• the tablets may be coated by methods well known in the art.
• Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
• Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
• the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
• Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
• compositions may take the form of tablets or lozenges formulated in conventional manner.
• the compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
• Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
• the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
• the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
• the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
• the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
• a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
• compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
• the pack or dispensing device may be accompanied by instructions for administration.
• the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
• Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
• the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
• Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.
• the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
• a bactericidal or fungicidal agent for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
• ophthalmic administration compounds may be formulated in an ointment such as petrolatum.
• the compounds of use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
• a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
• Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
• the quantity of a compound of use in the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g.
• the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):
• the leaving group L 1 is typically a halogen atom, e.g. chloro.
• the leaving group L 1 may be Ci_ 6 alkylsulfanyl, e.g. methylsulfanyl, or Ci_ 6 alkylsulfonyl, e.g. methylsulfonyl.
• the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. an organic nitrile such as acetonitrile, a lower alkanol such as ethanol, isopropanol or n-butanol, an ethereal solvent such as tetrahydrofuran or 1 ,4-dioxane, or an organic amide such as N,N-dimethylacetamide or l-methyl-2-pyrrolidinone.
• a suitable base e.g. an organic base such as N,N- diisopropylethylamine or l,8-diazabicyclo[5.4.0]undec-7-ene.
• the reaction may be performed in the presence of a transition metal catalyst.
• the transition metal catalyst is suitably a palladium-containing catalyst such as bis(tri-tert-butylphosphine)palladium(0).
• the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. an ethereal solvent such as 1,4-dioxane, typically in the presence of cesium carbonate.
• R 2a represents optionally substituted
• L represents a suitable leaving group
• B represents a boronic acid moiety -B(OH) 2 or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol; in the presence of a transition metal catalyst.
• the leaving group L is typically a halogen atom, e.g. bromo or iodo.
• the transition metal catalyst of use in the reaction between the compound of formula R 2a -B 1 and compound (V) is suitably a palladium-containing catalyst such as tetrakis(triphenylphosphine)palladium(0) or dichloro[l , 1 '-bis(diphenylphosphino)- ferrocene]palladium(II).
• a palladium-containing catalyst such as tetrakis(triphenylphosphine)palladium(0) or dichloro[l , 1 '-bis(diphenylphosphino)- ferrocene]palladium(II).
• reaction is conveniently carried out at an elevated temperature in a suitable solvent, e.g. an ethereal solvent such as 1,4-dioxane or 1,2-dimethoxyethane, typically in the presence of potassium phosphate, potassium carbonate or sodium carbonate.
• a suitable solvent e.g. an ethereal solvent such as 1,4-dioxane or 1,2-dimethoxyethane, typically in the presence of potassium phosphate, potassium carbonate or sodium carbonate.
• the intermediates of formula (V) may be prepared by reacting a compound of formula (IV) as defined above with a compound of formula (VI):
• An intermediate of formula (III) or (VI) wherein L 1 represents Ci_ 6 alkylsulfanyl, e.g. methylsulfanyl, may be converted into the corresponding compound wherein L 1 represents Ci_ 6 alkylsulfonyl, e.g. methylsulfonyl, by treatment with a suitable oxidising agent, e.g. 3-chloroperoxybenzoic acid.
• a suitable oxidising agent e.g. 3-chloroperoxybenzoic acid.
• L 3 represents a suitable leaving group
• the leaving group L is typically a halogen atom, e.g. chloro.
• the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as isopropanol or n-butanol, or an organic amide such as l-methyl-2-pyrrolidinone.
• a suitable solvent e.g. a lower alkanol such as isopropanol or n-butanol, or an organic amide such as l-methyl-2-pyrrolidinone.
• the reaction may be performed in the presence of a suitable base, e.g. an organic base such as N,N-diisopropylethylamine.
• a suitable solvent e.g. an ethereal solvent such as 1,4-dioxane.
• X, R 1 , R 3 , R 4 , L 1 and L 3 are as defined above; with a halogenating agent, e.g. elemental bromine or N-iodosuccinimide.
• a halogenating agent e.g. elemental bromine or N-iodosuccinimide.
• any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art.
• a compound comprising a N-BOC moiety may be converted into the corresponding compound comprising a N-H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
• a compound wherein R 1 represents halogen, e.g. chloro may be converted into the corresponding compound wherein R 1 represents amino (-NH 2 ) in a two-step procedure which comprises: (i) treatment with benzylamine; and (ii) removal of the benzyl moiety from the material thereby obtained by catalytic hydrogenation.
• a compound wherein R 1 represents halogen, e.g. chloro may be converted into the corresponding compound wherein R 1 represents amino (-NH 2 ) in a two-step procedure which comprises: (i) treatment with 4-methoxybenzylamine; and (ii) removal of the 4-methoxybenzyl moiety from the material thereby obtained by treatment with acid, e.g. an organic acid such as trifluoroacetic acid.
• a compound wherein R 1 represents -SR a may be converted into the corresponding compound wherein R 1 represents -S0 2 R a by treatment with an oxidising agent, typically 3- chloroperoxybenzoic acid (MCPBA).
• an oxidising agent typically 3- chloroperoxybenzoic acid (MCPBA).
• a compound wherein R 1 represents -S0 2 R a may be converted into the corresponding compound wherein R 1 represents -OR a by treatment with a sodium salt of formula NaOR a .
• a compound wherein R 1 represents -S0 2 R a e.g.
• methylsulfonyl may be converted into the corresponding compound wherein R 1 represents cyano by treatment with a cyanide salt, e.g. an alkali metal cyanide salt such as sodium cyanide.
• a compound wherein R 1 represents -S0 2 R a e.g. methylsulfonyl
• R 1 represents -NR b R c by treatment with an amine of formula H-NR b R c .
• a compound wherein R 1 represents -S0 2 R a e.g.
• methylsulfonyl may be converted into the corresponding compound wherein R 1 represents -NH 2 by treatment with ammonium hydroxide.
• a compound wherein R 1 represents -NR c COR d may be converted into the corresponding compound wherein R 1 represents -NHR C by treatment with a base, typically an alkali metal carbonate such as potassium carbonate.
• a compound wherein R 2 represents -C0 2 R d , in which R d is other than hydrogen, may be converted into the corresponding compound wherein R represents carboxy (-C0 2 H) by treatment with a base, typically an alkali metal hydroxide such as sodium hydroxide.
• a base typically an alkali metal hydroxide such as sodium hydroxide.
• a compound wherein R represents carboxy (-C0 2 H) may be converted into the corresponding compound wherein R 2 represents -CONR b R c or -CON(OR a )R b by treatment with the appropriate reagent of formula H-NR b R c or H-N(OR a )R b respectively.
• the reaction may typically be performed in the presence of a coupling agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and an additive such as 1-hydroxybenzotriazole hydrate (HOBT), optionally in the presence of a base, e.g. an organic base such as N,N-diisopropy lethy lamine.
• a coupling agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and an additive such as 1-hydroxybenzotriazole hydrate (HOBT)
• reaction may be performed in the presence of a coupling agent such as O-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU) and a base, e.g. an organic base such as N,N-diisopropy lethy lamine .
• a coupling agent such as O-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU)
• TBTU O-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate
• base e.g. an organic base such as N,N-diisopropy lethy lamine .
• a compound wherein R represents carboxy (-C0 2 H) may be converted into the corresponding compound wherein R represents -CONH 2 by treatment with ammonium chloride, typically in the presence of a coupling agent such as EDC and an additive such as HOBT, suitably in the presence of a base, e.g. an organic base such as diisopropylamine or N,N-diisopropy lethy lamine.
• a coupling agent such as EDC and an additive such as HOBT
• a base e.g. an organic base such as diisopropylamine or N,N-diisopropy lethy lamine.
• R represents -CONH 2 may be converted into the corresponding compound wherein R represents cyano (-CN) by treatment with phosphorus oxychloride.
• a compound wherein R represents -CONH 2 may be converted into the corresponding compound wherein R represents cyano in a two-step procedure which comprises: (i) treatment with cyanuric chloride; and (ii) treatment of the material thereby obtained with water.
• a compound wherein R represents carboxy (-C0 2 H) may be converted into the corresponding compound wherein R represents hydrogen by heating in the presence of a base, e.g. an organic amine such as triethy lamine.
• a base e.g. an organic amine such as triethy lamine.
• a compound wherein R represents carboxy (-C0 2 H) may be converted into the corresponding compound wherein R represents hydroxymethyl (-CH 2 OH) in a two-step procedure which comprises: (i) treatment with ethyl chloroformate and triethy lamine; and (ii) treatment of the material thereby obtained with a reducing agent, typically an alkali metal borohydride such as sodium borohydride.
• a reducing agent typically an alkali metal borohydride such as sodium borohydride.
• a compound wherein R represents carboxy (-C0 2 H) may be converted into the corresponding compound wherein R represents hydroxy in a two-step procedure which comprises: (i) treatment with diphenyl phosphoryl azide; and (ii) treatment of the material thereby obtained with water.
• a compound wherein R represents carboxy (-C0 2 H) may be converted into the corresponding compound wherein R 2 represents -NHC0 2 R d , wherein R d is other than hydrogen, in a two-step procedure which comprises: (i) treatment with diphenyl phosphoryl azide; and (ii) treatment of the material thereby obtained with the appropriate reagent of formula R d -OH.
• a compound wherein R represents carboxy (-C0 2 H) may be converted into the corresponding compound wherein R represents a 3-substituted l,2,4-oxadiazol-5-yl moiety in a two-step procedure which comprises: (i) treatment with an appropriately- substituted N'-hydroxyamidine derivative, typically in the presence of a coupling agent such as 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), suitably in the presence of a base, e.g.
• a coupling agent such as 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), suitably in the presence of a base, e.g.
• an organic base such as N,N-diisopropyl- ethylamine
• a strong base suitably a strong inorganic base, e.g. an alkali metal tert-butoxide such as potassium tert-butoxide.
• a compound wherein R represents 4,5-dihydrooxazol-2-yl may be prepared from the corresponding compound wherein R 2 represents -CONR b R c , in which R b represents -CH 2 CH 2 OH and R c represents hydrogen, by heating with a condensing agent such as N,N-diisopropylcarbodiimide, typically in the presence of copper(II) trifluoromethane- sulfonate.
• a condensing agent such as N,N-diisopropylcarbodiimide
• the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
• the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
• a racemate of formula (I) may be separated using chiral HPLC.
• a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
• a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode.
• the compounds in accordance with this invention potently inhibit the activity of human ⁇ .
• the reaction mixture was incubated for 60 minutes at room temperature.
• the ADP-GloTM Reagent was added and the plate was incubated for 40 minutes at room temperature, followed by addition of ADP-GloTM Detect Reagent.
• the plate was incubated for a further 120 minutes and read on a Luminescence plate reader.
• the data was fitted with XLfit from IDBS using model number 205.
• Compounds were assayed using a PI4Kbeta Adapta assay. Compounds were screened in 1% DMSO (final) as 3-fold serial dilutions from a starting concentration of 10 ⁇ .
• the 2X PI4KB (PI4K beta)/PI Lipid Kinase Substrate mixture was prepared in 50 mM HEPES pH 7.5, 0.1% CHAPS, 1 mM EGTA, 4 mM MgCl 2 .
• the final 10 ⁇ , Kinase Reaction consisted of 7.5-60 ng ⁇ 4 ⁇ , and 100 ⁇ PI Lipid Kinase Substrate in 32.5 mM HEPES pH 7.5, 0.05% CHAPS, 0.5 mM EGTA, 2 mM MgCl 2 .
• the final ATP concentration in the assay was 10 ⁇ .
• the detection mix consisted of EDTA (30 mM), Eu-anti-ADP antibody (6 nM) and ADP tracer.
• the detection mix contained the EC60 concentration of tracer for 5-150 ⁇ ATP.
• ATP was added to compound, followed by addition of a ⁇ 4 ⁇ / ⁇ Lipid Kinase Substrate mixture.
• the plate was shaken for 30 seconds to mix, then briefly centrifuged.
• the reaction mixture was incubated for 60 minutes at room temperature.
• the detection mix was added, then the plate was shaken and centrifuged.
• the plate was incubated for 60 minutes at room temperature and read on a fluorescence plate reader.
• the data was fitted with XLfit from IDBS using model number 205.
• Certain compounds in accordance with this invention are potent inhibitors when measured in the MLR test described below.
• MLR Mixed Lymphocyte Reaction
• PBMCs Human peripheral blood mononuclear cells
• Responder cells (0.12 x 106), Stimulator cells (0.045 x 106) and compounds (in different concentrations) were cocultured for 6 days in RPMI 1640 medium (BioWhittaker, Lonza, Belgium) supplemented with 10% fetal calf serum, 100 U/ml Geneticin (Gibco, LifeTechnologies, UK). Cells were cultured in triplicate in flat- bottomed 96-well microtiter tissue culture plates (TTP, Switzerland). After 5 days, cells were pulsed with 1 ⁇ iC ⁇ of methyl- H thymidine (MP Biomedicals, USA), harvested 18 h later on glass filter paper and counted.
• Proliferation values were expressed as counts per minute (cpm), and converted to % inhibition with respect to a blank MLR test (identical but without added compound).
• the IC 50 was determined from a graph with at least four points, each derived from the mean of 2 experiments. The IC 50 value represents the lowest concentration of test compound (expressed in ⁇ ) that resulted in a 50% inhibition of the MLR.
• Solvent A 10 mM ammonium formate in water + 0.1% ammonia solution
• Solvent B acetonitrile + 5% solvent A + 0.1 % ammonia solution
• Solvent A water + 0.1% formic acid
• Solvent B acetonitrile + 5% solvent A + 0.1 % ammonia solution

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• 2015
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